A critical step in the development of autoimmune diseases is the stimulation of immune cells against endogenous antigen. Here, we investigate soluble antigen arrays (SAgAs) capable of suppressing autoimmune response to antigen. When properly designed, these nanomaterials facilitate: 1) drainage to lymph nodes (site of antigen priming) and 2) multivalent presentation of both antigen and an immune cell adhesion inhibitor (to suppress immune response to the co- grafted antigen). Compelling preliminary data show that SAgAs significantly attenuated disease progression in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The objective of this study is to systematically study how the nanomaterial properties of SAgAs affect the local biodistribution and in vivo outcomes. Our central hypothesis is that, Targeted-SAgAs from 20-100 kDa will compartmentalize to regional lymph nodes and will significantly improve clinical outcomes and shift biomarkers towards immune tolerance. We propose four Specific Aims: Specific Aim #1: Synthesize and characterize Soluble Antigen Arrays (SAgAs). Specific Aim #2: Evaluate the therapeutic performance of SAgAs in EAE mice. Specific Aim #3: Identify the local biodistribution of SAgAs. Specific Aim #4: Define immune cells and soluble mediators that control EAE following treatment with the SAgAs. Nanomaterials that localize to lymph nodes and present antigens to induce immune tolerance represent an unexplored therapeutic approach for treating autoimmune diseases. This unique therapeutic approach addresses national health interests by firmly establishing the potential for innovative nanomaterial immunotherapies capable of inducing immune tolerance and extendable to novel vaccination schemes.